Bioactives From Brown Algae: Antioxidant, Anti-Inflammatory, Anticancer, and Antimicrobial Potential

2.1 Polysaccharides

Brown algae are a rich source of functional polysaccharides, comprising 20–76 % of their dry weight [²⁶]. Among these, fucoidans, laminarins, and alginates are the most prominent and well-studied (Fig. 1). These polysaccharides not only contribute to the resilience of algae in harsh marine environments but also exhibit bioactive properties such as antioxidant, antitumor, antibacterial, antiviral, and anti-inflammatory effects [^{9, 27, 28}].

2.2 Phenolic Compounds

Phenolic compounds are secondary metabolites characterized by an aromatic benzene ring with one or more hydroxyl groups attached directly to the ring, including any functional derivatives of these compounds [⁴⁷]. Brown algae have a higher concentration of phenolic compounds, particularly phlorotannins, than red and green algae [³⁴]. Besides phlorotannins, brown algae contain phenolic compounds such as phenolic acids and flavonoids (Fig. 2), which offer promising health-promoting properties, underscoring the significance of brown algae as a natural antioxidant source.

2.3 Pigments

Brown algae contain several photosynthetic pigments, including chlorophylls a and c, α-carotene, β-carotene, neoxanthins A and B, fucoxanthin, and violaxanthin [^{2, 62}]. Fucoxanthin, the predominant pigment responsible for their brown color, is essential for photosynthesis in deep marine environments with limited sunlight [⁶³]. Recent studies highlight fucoxanthin's health benefits, such as neutralizing free radicals, protecting cells from oxidative damage, and helping prevent chronic diseases such as cancer and cardiovascular disease [⁶⁴]. Consequently, fucoxanthin has attracted considerable interest. Fig. 3 shows the chemical structures of fucoxanthin and its metabolite fucoxanthinol.

2.4 Lipids

Brown algae are rich in bioactive lipids that contribute to their nutritional and medicinal properties. Among these lipids, polyunsaturated fatty acids (PUFAs) are particularly noteworthy, including essential omega-3 and omega-6 fatty acids, which are crucial for human health [⁷¹]. The lipid profile of brown algae also includes sterols like fucosterol, which exhibit a range of bioactivities, including antioxidant, anti-inflammatory, and anticancer effects. Fig. 4 shows the chemical structures of various lipids present in brown algae.

2.5 Micronutrients

3.1 Antioxidant Properties

Antioxidant bioactivity refers to the ability of certain substances to neutralize free radicals, which are unstable molecules that can cause cellular damage through oxidative stress. Oxidative stress, caused by an imbalance between free radicals and antioxidants, leads to cellular, protein, and deoxyribonucleic acid (DNA) damage and is implicated in numerous chronic conditions, including neurodegenerative disorders, cardiovascular disease, cancer, inflammation, diabetes, obesity, and various age-related diseases [⁸⁵]. Antioxidants mitigate damage by donating electrons to free radicals, neutralizing them, preventing their formation, scavenging them, or promoting their breakdown [⁸⁶]. They are also vital in food preservation and cosmetics. However, recent reports have highlighted the potential health hazards associated with synthetic antioxidants, including butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and tert-butylhydroquinone [⁸⁷]. Consequently, the search for effective and non-toxic natural compounds with antioxidant activity has intensified. Tab. 2 summarizes the antioxidant activity of various compounds from brown algae.

Fucoidans are increasingly recognized for their potent antioxidant effects. For instance, fucoidan from Sargassum polycystum shows significant antioxidant and anticancer effects, including high 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity and total antioxidant activity [⁸⁸]. Furthermore, fucoidan can outperform synthetic antioxidants like BHA, BHT, and ascorbic acid in scavenging superoxide anions and hydroxyl radicals, making it a potential ingredient for functional foods [^{89, 91}].

Laminarin also exhibits notable antioxidant properties. Ultrasonically extracted laminarin from Ascophyllum nodosum and Laminaria hyperborea demonstrated strong antioxidant activity, with DPPH inhibition levels of 93.23 % and 87.57 %, respectively [³⁸]. Additionally, laminarin effectively scavenged ROS, superoxide anions, and singlet oxygen, reducing the cytotoxicity caused by clinical drugs indomethacin and dabigatran. This highlights laminarin's potential as a therapeutic agent for oxidative stress-related conditions [⁹²].

Alginates also exhibit significant antioxidant properties, with their activity influenced by factors such as season and molecular mass [⁹³]. For example, sodium alginates have demonstrated notable antioxidant effects, including significant DPPH radical-scavenging activity (74 % inhibition at 0.5 mg mL⁻¹), considerable ferric reducing potential, effective hydroxyl radical-scavenging activity (82 % at 5 mg mL⁻¹), and strong DNA protection [⁹⁴]. Furthermore, purified sodium alginate from Sargassum vulgare demonstrated high hydroxyl radical-scavenging activity (∼92 % at 2 mg mL⁻¹), comparable to that of standard antioxidants [⁹⁵].

Phlorotannins are also potent antioxidants because they can scavenge free radicals, inhibit ROS production, and activate antioxidant defense mechanisms [^{11, 96}]. For example, phlorotannins from Cystoseira compressa have shown significant high free radical-scavenging activity and improved antioxidant capacity, serum insulin, and hepatic glutathione levels in diabetic rats, reducing oxidative damage in pancreatic β cells [⁹⁷]. Remarkably, the antioxidant capacity of phlorotannins decreases as their molecular mass increases [⁹⁶]. Therefore, further studies are needed to fully explore the relationship between molecular weight and bioactivity to harness their therapeutic potential.

Phenolic acids and flavonoids in brown algae significantly contribute to the antioxidant activity of algae extracts [⁹⁸]. For instance, Padina tetrastromatica contains phenolic compounds and flavonoids (including danshensu, quercetin derivative, luteolin, genistein, and hydroxyl-ferulic acid derivative) with strong antioxidant activities [⁹⁹]. Interestingly, a study on commercial algal food products found that some algal products are promising functional foods rich in polyphenols [¹⁰⁰]. This study identified epicatechin as the most abundant phenolic compound and found a strong correlation (r = 0.99) between phenolic content and antioxidant capacity.

Furthermore, another critical antioxidant in brown algae is fucoxanthin. Fucoxanthin can reduce kidney damage caused by oxidative stress in mice by activating the silent information regulator 1/nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Sirt1/Nrf2/HO-1) signaling pathway, which is a crucial cellular mechanism involved in protecting cells against oxidative stress and inflammation [¹⁰¹]. Furthermore, fucoxanthin provides significant neuroprotection in traumatic brain injury models by activating the Nrf2-antioxidant-response and Nrf2-autophagy pathways, which are critical in reducing neuronal apoptosis and oxidative stress [¹⁰³]. Notably, its heat-stable antioxidant properties enhance its practical applications under various processing and storage conditions [⁶⁴].

Despite the low lipid content of brown algae, they contain valuable compounds with potent antioxidant properties. For instance, the lipid profiles of Bifurcaria bifurcata and invasive Sargassum muticum revealed numerous lipid species, including glycolipids, phospholipids, and betaine lipids, with significant antioxidant properties [¹⁰⁴]. Similarly, a study comparing the lipid profiles of 5 commonly consumed Japanese dietary algae found 304 molecular species with significant antioxidant properties [¹⁰⁶]. These findings highlight the potential of dietary algae as antioxidants and health-promoting foods.

In addition to these lipids, fucosterol demonstrates impressive antioxidant effects. Fucosterol ameliorates oxidative stress induced by tert-butyl hydroperoxide and tacrine in HepG2 cells, reducing intracellular ROS and increasing glutathione levels [¹⁰⁸]. In another study, fucosterol inhibited lipid peroxidation by more than 50 %, confirming its potent antioxidant activity. [¹⁰⁹]. It also reduced oxidative stress in human dermal fibroblasts stimulated with tumor necrosis factor-alpha (TNF-α) and interferon-gamma by decreasing intracellular ROS production and upregulating Nrf2 and HO-1 signaling, highlighting its therapeutic potential [¹¹⁰].

Vitamins A, C, and E possess significant antioxidant properties. Vitamin A, through its metabolite all-trans-retinoic acid, indirectly regulates the expression of genes involved in antioxidant responses, whereas vitamin E inhibits lipid peroxidation, and vitamin C protects biomolecules from oxidative damage [^111-113]. Moreover, brown algae are rich in iodine, a mineral that neutralizes free radicals, induces type II antioxidant enzymes, and inactivates pro-inflammatory pathways [¹¹⁴]. These vitamins and minerals make brown algae a valuable source of natural antioxidants.

3.2 Anti-Inflammatory Properties

Inflammation is a complex defense mechanism against various types of tissue injury, including traumatic, infectious, post-ischemic, toxic, or autoimmune causes [¹¹⁵]. Usually, inflammation aids recovery by destroying harmful agents and promoting tissue repair. However, prolonged inflammation can contribute to the pathogenesis of many diseases [¹¹⁶]. Although not the primary cause of conditions like obesity, neurodegenerative diseases, atherosclerosis, cancer, asthma, inflammatory bowel disease, multiple sclerosis, or rheumatoid arthritis, non-resolving inflammation significantly influences their progression [¹¹⁷]. Therefore, the challenge lies in developing more effective, less toxic treatments to manage both acute and chronic inflammatory conditions [¹¹⁸]. Tab. 3 summarizes the anti-inflammatory activity of various bioactive compounds from brown algae.

Multiple studies have demonstrated fucoidan's anti-inflammatory effects. For instance, in a mouse model of acute colitis, oral administration of a fucoidan-polyphenol complex and purified fucoidan significantly reduced colitis symptoms, inflammation, and cytokine production [¹²⁰]. These findings suggest its potential for treating inflammatory bowel diseases like ulcerative colitis and Crohn's disease. Furthermore, fucoidan extracts significantly inhibited pro-inflammatory cytokine production in immune cells without cytotoxicity, with the most substantial effects seen in low-molecular-weight fractions, particularly from M. pyrifera [¹²¹]. Fucoidan's anti-inflammatory mechanisms involve blocking lymphocyte adhesion, enzyme inhibition, apoptosis induction, and downregulation of inflammatory pathways like mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [⁹].

Laminarin also possesses significant anti-inflammatory properties. It protects skin cells from oxidative stress and inflammation induced by environmental factors by modulating glycan and receptor interactions on the cell surface [¹²³]. Moreover, topical application of laminarin significantly reduced inflammation, epidermal and dermal thickening, mast cell infiltration, and serum immunoglobulin E levels in a mouse dermatitis model [¹²⁴]. Laminarin also suppressed the protein levels of pro-inflammatory cytokines, including interleukin-1 beta (IL-1β), TNF-α, monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1 alpha (MIP-1α).

Similarly, alginates effectively modulate inflammatory responses. For instance, alginate-derived seleno-polymannuronate reduced NO, prostaglandin E2 (PGE2), and ROS production and decreased inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in lipopolysaccharide (LPS)-activated murine macrophage cells [¹²⁷]. It also inhibited pro-inflammatory cytokines and blocked the pro-inflammatory NF-κB and MAPK signaling pathways. Furthermore, oral administration of alginate oligosaccharide reduced pro-inflammatory cytokines IL-1β and interleukin-6 (IL-6) in osteosarcoma patients [¹²⁸]. Guluronate oligosaccharides from alginate further lowered the production of inflammatory molecules (NO, PGE2, and ROS) and blocked key signaling pathways involved in inflammation (NF-κB and MAPK) [¹²⁹]. All these findings indicate that alginate may have promising therapeutic applications in various medical fields.

Likewise, phlorotannins have demonstrated potent anti-inflammatory activities. For instance, a phlorotannin-rich extract downregulated iNOS, COX-2, TNF-α, IL-6, and high mobility group box 1 (HMGB1) and suppressed the NIK/TAK1/IKK/IκB/NFκB pathway while increasing Nrf2 and HO-1 expression [¹³¹]. Moreover, the phlorotannin 8,8′-bieckol suppressed NO, PGE2, and IL-6 production by inhibiting the NF-κB pathway and reducing ROS production [¹³²]. When orally administered to mice, six purified phlorotannins significantly suppressed ear swelling, indicating anti-allergic and anti-inflammatory effects [¹³⁴]. These findings suggest that phlorotannins could be developed as functional foods or anti-inflammatory drugs.

Flavonoids and phenolic acids exhibit potent anti-inflammatory effects, primarily by inhibiting pro-inflammatory cytokine production. A study on extracts rich in these compounds, including phloroglucinol and gallic acid, demonstrated significant inhibition of NO, interleukin-1 alpha (IL-1α), IL-6, COX-2, and iNOS in LPS-stimulated RAW 264.7 macrophages [¹³⁵]. Moreover, kaempferol also reduces skin inflammation in psoriasis by decreasing T-cell infiltration and the expression of pro-inflammatory cytokines like IL-6 and TNF-α [¹³⁶].

Fucoxanthin is another potent anti-inflammatory compound. It suppresses pro-inflammatory enzymes and genes, blocking protein kinase B (Akt)/NF-κB and MAPKs/Activator protein 1 (AP-1) pathways while enhancing Nrf2 activation and HO-1 expression [¹³⁷]. In mice, fucoxanthin (50 and 100 mg kg⁻¹ day⁻¹) protected against dextran sulfate sodium-induced colitis, preventing weight loss, reducing disease activity, and ameliorating colon shortening and histological damage [¹³⁸]. Fucoxanthin also decreased colonic PGE2 levels and COX-2 and NF-κB overexpression, showing potential in treating ulcerative colitis. Similarly, fucoxanthin inhibited inflammatory mediators and reduced phosphorylation of key signaling proteins, including MAPK, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38, and Akt [¹³⁹].

Algae-derived lipids, particularly omega-3 long-chain PUFAs, reduce inflammatory markers, cytokines, and NO [¹⁴⁰]. For example, monogalactosyl diacylglycerols from Fucus spiralis and a lipid fraction from Sargassum ilicifolium (formerly Sargassum cristaefolium) significantly reduced NO production in RAW 264.7 macrophage cells [^{141, 142}]. These findings suggest that algae-derived lipids could be developed as functional food ingredients or supplements to combat chronic inflammation.

Furthermore, fucosterol also shows significant anti-inflammatory effects. Fucosterol from Padina boryana reduced particulate matter-induced inflammation in RAW 264.7 macrophages by reducing oxidative stress and inflammatory responses by inhibiting iNOS, COX-2, and pro-inflammatory cytokines and regulating the NF-κB, MAPKs, and Nrf2/HO-1 pathways [¹⁴⁴]. Moreover, oral administration of fucosterol (200 mg kg⁻¹ day⁻¹) reduced atopic dermatitis-like lesions in mice, indicating its potential for treating inflammatory skin diseases [¹⁴⁵].

Vitamins and minerals in brown algae can support inflammation management. For example, vitamin A, known as the “anti-inflammation vitamin,” enhances the body's anti-inflammatory response [¹⁴⁶]. Vitamin E supplementation reduces oxidative stress and inflammation markers [¹⁴⁷]. Moreover, vitamin C, essential for regenerating other antioxidants like vitamin E, also reduces inflammation by inhibiting NF-κB activation, a key regulator of various inflammatory genes [¹¹³]. Moreover, some studies have shown that topical application of iodine and iodide can activate the Nrf2 pathway in human skin, protecting against ultraviolet B (UVB)-induced damage and reducing pro-inflammatory cytokines [¹⁴⁸]. Therefore, ensuring adequate intake of these nutrients may help modulate inflammation and lower the risk of chronic inflammatory diseases. However, more research is needed to understand their anti-inflammatory mechanisms.

3.3 Anticancer Properties

Cancer is a complex disease with many potential causes, including smoking, occupational exposure, poor diet, genetics, and environmental pollution [^{149, 150}]. Treatments, like surgery, radiotherapy, and chemotherapy, often come with significant side effects that limit their efficacy. Historically, various chemicals, from conventional agents like methotrexate and folic acid analogs to newer compounds such as anthracyclines, have been used in cancer therapy [^{151, 152}]. However, these agents can cause severe toxicity, including bone marrow suppression, gastrointestinal damage, pancytopenia, hepatotoxicity, cardiomyopathy, and congestive heart failure [^153-155]. Moreover, these agents may lead to drug resistance over time, reducing their effectiveness [¹⁵⁶]. Consequently, there is growing interest in natural compounds with lower toxicity and fewer side effects. Brown algae, rich in bioactive compounds with significant anticancer properties, are particularly promising. Tab. 4 summarizes the anticancer activity of various bioactive compounds from brown algae.

Fucoidan has recently gained significant attention for its antitumor properties and effects against multiple types of cancer. Fucoidan can delay tumor growth, induce tumor cell death, and act synergistically with chemotherapeutic agents [¹⁵¹]. Additionally, it inhibits angiogenesis, which is crucial for tumor growth and metastasis [¹⁵⁷]. Fucoidan induces apoptosis in lymphoma cells via caspase and ERK pathways [¹⁵⁸]. It also suppresses metastasis by targeting factors like vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) [¹⁵⁹]. This is particularly important as metastasis, the process through which cancer cells spread to different body areas, accounts for up to 90 % of cancer-related fatalities [¹⁹²].

Similarly, laminarin and its sulfated derivatives can inhibit the proliferation and migration of human colorectal adenocarcinoma, melanoma, and breast adenocarcinoma cells [¹⁶⁰]. Laminarin also enhances radiation therapy for melanoma, protecting normal epidermal cell walls while exhibiting significant anticancer activity [¹⁶¹]. Notably, sulfated laminarin sensitized melanoma cells to X-ray irradiation; thus, combining sulfated laminarin with X-ray therapy may offer a promising treatment for melanoma. Laminarin also suppresses ovarian cancer cell growth and cell cycle progression, inducing cell death via DNA fragmentation, ROS generation, apoptotic signals, endoplasmic reticulum stress, calcium level regulation, and endoplasmic reticulum-mitochondria axis alteration, all without cytotoxicity [¹⁶²].

Brown algae-derived alginates have also shown promise in cancer treatment. Alginates are valuable for developing new anticancer drug delivery systems due to their biocompatibility, biodegradability, strong bioadhesion, and ability to load and deliver proteins, enabling the development of new “smart” polymers [¹⁶³]. Alginates improve the cost-effectiveness and safety of cancer treatments by facilitating precise drug delivery and release control. For instance, polydopamine nanoparticles (NPs) coated with sodium alginate improve the water solubility, oral bioavailability, and tumor targeting of gambogenic acid, an anticancer compound [¹⁶⁴]. Similarly, calcium alginate NPs improve the delivery of curcumin and resveratrol, two polyphenolic compounds with anticancer properties but limited solubility and bioavailability [¹⁶⁶]. This demonstrates that alginate can improve the clinical use of hydrophobic anticancer drugs, suggesting that alginate-based delivery systems have significant potential to advance cancer therapies.

Phlorotannins also exhibit potent anticancer properties. The phlorotannin dieckol significantly inhibits movement and migration-related gene expression in MCF-7 human breast cancer cells [¹⁶⁷]. It also demonstrates cytotoxic effects on A2780 and SKOV3 ovarian cancer cells, induces apoptosis in SKOV3 cells, and suppresses tumor growth in mice without significant adverse effects [¹⁶⁸]. Phlorotannins may also help prevent skin cancer and mitigate radiation-induced tissue damage. Moreover, diphlorethohydroxycarmalol (DPHC), a phlorotannin extracted from brown algae, protects skin cells from UVB-induced DNA damage by reducing harmful DNA changes and activating cellular repair mechanisms [¹⁶⁹].

Brown algae are rich in phenolic compounds and flavonoids with anticancer potential. A study identified flavone, a flavonoid, as a potent antioxidant and anticancer agent with strong free radical-scavenging activity and significant anti-proliferation effects in breast cancer cells [¹⁷¹]. Flavone can kill cancer cells by inducing apoptosis, interrupting the cell cycle, reducing the expression of the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2), and preventing metastasis by suppressing the activity of MMPs. Additionally, two polyphenolic molecules in Fucus vesiculosus have shown significant cytotoxicity against human pancreatic cancer cells [¹⁷²].

Fucoxanthin, a natural carotenoid from brown algae, also has potent anticancer properties. Both fucoxanthin and its metabolite, fucoxanthinol, exert anticancer effects through various mechanisms, including anti-proliferation, cell cycle arrest, apoptosis induction, anti-metastasis, and tumor inhibition [^{12, 173}]. Both significantly reduce cell viability in various colorectal cancer cell lines, with fucoxanthinol being the most effective [¹³]. Additionally, fucoxanthinol outperformed the standard chemotherapy drugs fluorouracil and paclitaxel in shrinking tumors. Fucoxanthin induces apoptosis in endometrial and human cervical cancer cells by modulating key signaling pathways, including the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway [^{174, 175}].

Moreover, DHA and EPA exhibit significant anticancer activity in multiple myeloma cells and can enhance the efficacy of bortezomib, although the administration timing is crucial [¹⁷⁶]. Moreover, these omega-3 fatty acids inhibit PGE2 production, contributing to their anticancer effects [¹⁷⁷]. Additionally, these PUFAs may help protect against colorectal, breast, prostate, and digestive system cancers by modulating gene expression, inhibiting tumor growth, inducing apoptosis, and reducing inflammation [¹⁷⁸].

Fucosterol has demonstrated significant cytotoxic and anti-proliferative effects against cancer cell lines (Hep-2, SiHa, and MCF-7), with 50 % cytotoxicity concentrations ranging from 3.1 to 25.6 µg mL⁻¹, and a strong preference for cancer cells over normal cells [¹⁸⁰]. In colorectal cancer, fucosterol reduces cell viability, both alone and in combination with the chemotherapeutic agent 5-fluorouracil, without harming normal cells [¹⁸¹]. This combination also inhibits cell proliferation and migration, suggesting that fucosterol could enhance chemotherapy efficacy for colon cancer. Additionally, a study revealed that fucosterol potentiated the cytotoxic effect of the anticancer drug doxorubicin in triple-negative breast cancer cells [¹⁸³]. However, these effects were not replicated in three-dimensional cultures, indicating the need for more complex models in drug screening.

The evidence on the role of vitamins and minerals in cancer prevention and treatment is mixed. Although a nutrient-rich diet is essential for overall health and may reduce cancer risk, specific findings on vitamins are inconclusive [¹⁸⁴]. Vitamins A, C, and E, known for their antioxidant properties, may help prevent oxidative stress, potentially contributing to cancer prevention. Notably, chemotherapy patients often exhibit low vitamin C levels, and some studies suggest that supplementation might improve immunity, cancer survival, clinical status, and quality of life [^{185, 186}]. However, the results are mixed, with some studies associating vitamins A, C, and E supplementation with both increased and decreased cancer risk [¹⁸⁷].

Iodine, a mineral abundantly found in brown algae, has also been studied for its cancer-related effects. Although correcting iodine deficiency may help prevent cancer, excessive intake could increase thyroid cancer risk [¹⁸⁸]. Nonetheless, some promising studies suggest that vitamin C and iodine could serve as coadjuvants in cancer treatment [^{189, 190}]. Overall, the role of these micronutrients in cancer prevention and treatment remains an active area of investigation, and further phase II and III clinical trials are needed to establish their therapeutic potential.

3.4 Antimicrobial Properties

Antimicrobial activity refers to a substance's ability to inhibit or destroy microorganisms such as bacteria, fungi, and viruses. This is essential for combating infections and developing new antimicrobial agents, particularly in response to the growing issue of antibiotic resistance. Antibiotic resistance occurs when bacteria evolve to survive drugs intended to eliminate them, leading to ineffective treatments and persistent infections [¹⁹³]. This resistance significantly compromises antibiotic efficacy, increasing morbidity, mortality rates, and healthcare costs, posing a serious global health threat that underscores the need for novel antimicrobials [¹⁹⁴]. Moreover, developing new antiviral compounds is crucial for addressing emerging and existing global health threats, as evidenced by the coronavirus disease 2019 (COVID-19) pandemic. Despite the success of vaccines, the emergence of variants and breakthrough infections underscores the need for new antiviral agents to address evolving strains and resistance mechanisms [¹⁹⁵]. Similarly, discovering new antifungal compounds is crucial due to the increasing incidence of fungal infections, limited effective antifungal drugs, and increasing resistance among fungal pathogens. Fungal infections, particularly those caused by Cryptococcus neoformans and Candida albicans, affect over 1.4 million individuals annually, with high mortality rates, especially among immunocompromised individuals, such as human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome patients [¹⁹⁶]. Moreover, the current antifungal treatments are often limited by high toxicity and the frequent development of resistance [¹⁹⁷].

Natural products, particularly those derived from marine organisms, are increasingly recognized for their antimicrobial properties [¹⁹⁸]. Among these, brown algae are a promising source of bioactive compounds with significant antimicrobial activity against various pathogens, including foodborne bacteria, highlighting the potential of brown algae as a valuable source of natural antimicrobial agents. Tab. 5 summarizes the antimicrobial activity of various bioactive compounds from brown algae.

Fucoidans from brown algae are potent antimicrobial agents. Fucoidan from F. vesiculosus effectively suppressed biofilm formation and planktonic cell growth of Streptococcus mutans and Streptococcus sobrinus, major contributors to tooth decay, at concentrations above 250 µg mL⁻¹; however, it did not eliminate established biofilms [¹⁹⁹]. It also exhibited bacteriostatic and bactericidal effects against Listeria monocytogenes and Salmonella Typhimurium, with effectiveness dependent on concentration, temperature, and exposure time [²⁰¹]. This activity was validated in a pasteurized apple beverage, where fucoidan at 25–100 µg mL⁻¹ inhibited both pathogens. Furthermore, fucoidan can inhibit viral attachment and replication while also triggering an immune response against viral infections, suggesting its potential against COVID-19 [²⁰²].

Laminarins, another group of marine-derived polysaccharides, also exhibit significant antimicrobial properties. For instance, a laminarin-based wound-healing cream showed antibacterial and antioxidant effects, promoting 98.57 % wound contraction in rats after 13 days, with improved collagen deposition, fibroblast activity, and vascular density compared to controls [²⁷]. Laminarin also exhibits significant antibacterial activity against Staphylococcus aureus, L. monocytogenes, Escherichia coli, and S. Typhimurium [³⁸]. Additionally, a laminarin-based formulation reduced the severity of the wheat pathogen Zymoseptoria tritici by 42 % and lowered the density of pycnidia (spore-producing fungal structures) by 45 %. This effect was achieved through direct antifungal activity and the elicitation of defense-related genes with minimal metabolic cost to the plant [²⁰⁴].

Alginates are widely used due to their gelling properties. However, they also exhibit antimicrobial properties, especially when combined with other antimicrobial agents or chemically modified. For example, low-molecular-weight alginate oligosaccharides inhibit the growth of Pseudomonas aeruginosa by modulating its quorum sensing system, thereby reducing biofilm formation and resistance to the antibiotic azithromycin [²⁰⁵]. Additionally, oxidized sodium alginate condensed with o-phenylenediamine analogs showed antimicrobial activity against various fungi (e.g., Aspergillus niger, Aspergillus flavus, and C. albicans) and bacteria (e.g., Staphylococcus epidermidis, methicillin-resistant S. aureus, S. Typhimurium, and Proteus vulgaris) with inhibition zones reaching up to 37.60 mm [²⁰⁶].

Phlorotannins also combat various pathogens by binding to bacterial proteins, disrupting oxidative phosphorylation, altering cell permeability, and causing bacterial cell death [²⁰⁸]. Phlorotannins from Eisenia bicyclis exhibited significant activity against L. monocytogenes, with minimum inhibitory concentration (MIC) values of 16–256 µg mL⁻¹. Among these, fucofuroeckol-A demonstrated the highest potential, with MIC values of 16–32 µg mL⁻¹, and exhibited synergistic effects with streptomycin against drug-resistant L. monocytogenes strains [²⁰⁹]. Phlorotannins also displayed high antibiotic activity, with low MIC values (4–25 µg mL⁻¹) against bacteria and yeast [²¹⁰].

Other phenolic compounds and flavonoids in brown algae also exhibit antimicrobial properties. For example, ethanol extracts from Sargassum wightii and Halimeda gracilis significantly inhibited biofilm formation by Gram-negative bacteria and exhibited potent insecticidal effects against mosquito larvae, suggesting potential for developing biodegradable pesticides and antimicrobial agents [²¹³]. Furthermore, flavonoids extracted from C. compressa and Padina pavonica using microwave-assisted extraction exhibited significant antibacterial activity against multidrug-resistant bacteria isolated from various food products [²¹⁵]. This suggests that flavonoids hold promising potential as natural antibacterial agents.

Fucoxanthin also exhibits notable antibacterial effects, particularly against Gram-positive bacteria. A study revealed that fucoxanthin inhibited the growth of 13 aerobic bacteria, including Streptococcus agalactiae, S. epidermidis, and S. aureus, but had no activity against strict anaerobic bacteria [²¹⁶]. Moreover, fucoxanthin exhibited strong antitubercular activity against Mycobacterium tuberculosis with MICs between 2.8 and 4.1 µM, selectively targeting two key enzymes in the cell wall biosynthesis and achieving over 98 % inhibition, showing superior selective toxicity compared to the standard drug isoniazid [²¹⁷]. Fucoxanthin also inhibited severe acute respiratory syndrome coronavirus two infection in Vero cells in a concentration-dependent manner without cytotoxicity, indicating its potential as a treatment for coronavirus infection [²¹⁸].

PUFAs like DHA and EPA also have remarkable antimicrobial properties. For instance, a recent study demonstrated their significant antibacterial and antibiofilm activities against multiple drug-resistant Staphylococcus strains [²¹⁹]. Similarly, DHA and EPA have been found effective against periodontal pathogens, inhibiting planktonic growth and biofilm formation of Porphyromonas gingivalis and restraining Fusobacterium nucleatum at higher concentrations [²²⁰]. Additionally, PUFA-rich lipid extracts from Undaria pinnatifida showed strong antibacterial effects against Vibrio species [²²¹]. Therefore, with their rich content of omega-3 and omega-6 fatty acids, brown algae could be a promising source of new natural antimicrobial agents.

Moreover, modified fucosterol compounds exhibited notable antibacterial properties against Klebsiella pneumoniae, E. coli, P. aeruginosa, S. mutans, and S. aureus [²²²]. This study showed that fucosterol derivatives can bind to bacterial proteins, highlighting their potential in combating multidrug-resistant strains. Furthermore, fucosterol exhibited antifungal properties, completely inhibiting the growth and causing degradation of Fusarium culmorum macronidia at 1.0 % concentration, while inducing structural changes at lower concentrations (0.05–0.2 %) [²²³]. Furthermore, the bioactivity, safety, and toxicity of fucosterol have been reviewed, highlighting its potential as a natural antibacterial agent for medical and industrial applications [²²⁴].

Although vitamins are not antibacterial agents, they support the immune system, indirectly aiding in the fight against bacterial infections [²²⁵]. In contrast, the minerals in brown algae, particularly iodine, exhibit potent, broad-spectrum antimicrobial properties against bacteria, viruses, and fungi [²²⁶]. Unlike antibiotics that follow specific molecular pathways, iodine penetrates cell walls rapidly, altering bacterial functions and structures, making it less susceptible to resistance [²²⁷]. Consequently, various iodine formulations, such as iodine-loaded polymeric membranes and iodine-doped materials, have been developed to harness its antimicrobial potential for different applications, including wound healing, surgical sutures, and medical implants [^228-230]. Therefore, iodine remains a valuable and versatile antimicrobial agent in modern medicine. Beyond iodine, minerals like zinc and selenium in brown algae also exhibit antimicrobial activity by disrupting microbial metabolism and enhancing host immune responses [^{231, 232}]. This multifaceted antimicrobial action underscores the potential of brown algae as a natural source of compounds for developing novel antimicrobial agents.

4.1 Pharmaceutical and Medical Applications

The pharmaceutical and medical industries can greatly benefit from brown algae's bioactive compounds, which exhibit antioxidant, anti-inflammatory, antimicrobial, and anticancer properties [²⁰]. These compounds can mitigate oxidative stress, potentially preventing premature aging, enhancing immunity, and helping treat or prevent chronic diseases such as diabetes, cardiovascular diseases, and certain cancers. Furthermore, their anti-inflammatory effects could revolutionize treatments for chronic inflammatory conditions like rheumatoid arthritis, chronic kidney disease, asthma, psoriasis, multiple sclerosis, and inflammatory bowel diseases like Crohn's disease and ulcerative colitis [^{136, 138, 233}]. Additionally, their anticancer potential could lead to safer, less toxic alternatives to conventional treatments.

In the realm of antimicrobial applications, brown algae's bioactive compounds could be crucial in combating antibiotic-resistant pathogens, a major global health threat. Although no algae-derived drugs have been approved by the US Food and Drug Administration, the Chinese Food and Drug Administration approved the use of a fucoidan-based drug called Haikun Shenxi for the clinical treatment of chronic kidney disease in 2003 [²³³]. The fucoidan-based product PERIDAN has also shown effectiveness in preventing post-operative abdominal adhesions in rats [²³⁴]. Moreover, fucoidan-based supplements like UMI No Shizuku, Doctor's Best Fucoidan, and Fucoidan Force are marketed for their immune-boosting, antioxidant, antiviral, and anticancer benefits [^235-237]. Similarly, FucoThin, a fucoxanthin-containing supplement, is promoted as a weight loss aid [²³⁸]. Algae-based omega-3 supplements also provide a sustainable, vegan-friendly source of essential fatty acids.

Moreover, alginates are used in wound dressings like Algisite M and Maxorb II for their gel-forming abilities and in medications like Gaviscon for gastrointestinal issues [^239-241]. They are also used for dental molds and controlled-release agents in pharmaceuticals. Future applications could include advanced drug delivery systems, such as chitosan–alginate NPs for antiviral drug administration [²⁴²]. Furthermore, their biocompatibility and healing-promoting properties are leading to new surgical applications, including sutures, sealants, and filling materials [^{243, 244}].

Although algae-based medicines are still emerging, the success of existing products and ongoing research suggests a promising future for brown algae-derived compounds in both medical and commercial applications. Continued investment and research will likely yield new treatments and a deeper understanding of the health benefits of these marine resources.

4.2 Cosmetic Applications

The cosmetics industry could significantly benefit from the bioactive compounds in brown algae. These compounds offer a variety of properties that could drive the development of new personal care and beauty products. For example, the antioxidant compounds in brown algae can protect the skin from free radical damage, potentially delaying skin aging. Similarly, their anti-inflammatory properties can be harnessed in creams or lotions for treating inflammatory skin conditions like acne, rosacea, psoriasis, and dermatitis by reducing inflammation and irritation.

Compounds, such as fucoidan, fucoxanthin, laminarin, alginate, and phlorotannins, are particularly promising due to their moisturizing, rejuvenating, anti-wrinkle, antioxidant, anti-inflammatory, and photoprotective effects [^{245, 246}]. These UV-protective properties could be incorporated into personal care and beauty products to help prevent sun damage and its harmful effects, including photoaging and skin cancer. Moreover, as fucoidan has been shown to improve skin elasticity, firmness, and gloss, as well as improve hair protection, growth, and shine, it could be used in various cosmetic products [²⁴⁷]. In addition, the antimicrobial properties of these compounds could serve as natural preservatives in personal care and beauty products. For example, a recent study highlighted alginate's potential as a preservative in cosmetics due to its antimicrobial activity [²⁴⁸]. These antimicrobial compounds could also help develop products to keep skin clean and healthy by combating pathogens that cause infections and other skin problems. Notably, with increasing consumer demand for sustainable products, the biodegradable and natural aspects of algae compounds could be emphasized in marketing these products.

Several algae-derived compounds are already in use in the cosmetics industry. For instance, alginates are widely used as thickening, encapsulating, moisturizing, and stabilizing agents [²⁴⁹]. Notable examples include La Mer cream, which incorporates kelp-derived compounds [²⁵⁰]. Similarly, Oceanium offers a cosmetics line featuring fucoidan from Saccharina latissima [²⁵¹]. The French company Phytomer is a pioneer in incorporating marine-derived compounds into its cosmetic products [²⁵²]. Furthermore, Seaflora also offers a range of products that leverage the anti-inflammatory and antibacterial properties of these bioactives to treat skin conditions like acne, rosacea, eczema, and psoriasis [²⁵³]. Lastly, the multinational BASF has developed Seanactiv, a formulation containing F. vesiculosus extracts, designed to rejuvenate the eye contour [²⁵⁴].

4.3 Food Industry Applications

Brown algae serve as a versatile resource in the food industry, offering a range of functional and nutritional benefits that go beyond conventional uses. Alginate from brown algae is widely used in the food industry as a thickening, gelling, and stabilizing agent. Brown algae also provide vitamins, minerals, and fatty acids, improving the nutritional profile of foods. For instance, the New Zealand company Pacific Harvest markets seasonings based on the brown algae Ecklonia radiata, promoting them as a salt substitute rich in iodine [²⁵⁵]. Additionally, antioxidant, anticancer, and anti-inflammatory compounds, like fucoidan, fucoxanthin, and phlorotannins, could be incorporated into functional foods and nutraceuticals to prevent chronic diseases [²⁵⁶]. These compounds also show promise as preservatives, with studies successfully incorporating brown algae extracts into beverages and foods for this purpose [^{201, 257}]. These new preservatives could replace traditional ones linked to health concerns. In addition, compounds, such as fucoidan and phlorotannins, could be used to develop antimicrobial edible coatings for fruits, vegetables, and other perishable foods to extend their shelf life [²⁵⁸]. Brown algae are also an excellent source of dietary fiber, promoting digestive health by supporting intestinal regularity and beneficial gut bacteria. Incorporating these compounds into food products can aid digestion, offer prebiotic benefits, and contribute to satiety, making them valuable for weight management and metabolic health. For instance, alginates have been shown to induce satiety and resist digestion in the stomach, suggesting their utility in weight management [²⁵⁹]. Furthermore, the potential of algae extends beyond food products to innovative packaging solutions, as evidenced by the biodegradable algae-based packaging developed by the company Notpla [²⁶⁰]. Lastly, with the growing demand for plant-based dietary options, algae offer sustainable, vegan alternatives to animal-based ingredients, promoting more responsible food practices.

4.4 Current Market Value

The global market for algae-derived bioactive compounds has grown substantially over the past decade, driven by increasing demand in pharmaceuticals, nutraceuticals, cosmetics, and food and beverages. The algae extract market alone was valued at USD 5.42 billion in 2023 and is projected to grow at a compound annual growth rate (CAGR) of 7.2 % from 2024 to 2032, reaching USD 9.44 billion by 2032 [¹⁹]. Additionally, the World Bank's 2023 report on “Global Algae New and Emerging Markets” states that the marine-derived pharmaceutical market, valued at $2.56 billion in 2022, is expected to grow at a 5–10 % CAGR from 2022 to 2030 [²⁶¹]. On the basis of these growth rates, the market is projected to reach between approximately $3.78 billion and $5.49 billion by 2030. Fig. 5 illustrates the market values of different bioactive compounds from brown algae for 2023 and their projections.

In 2023, the global market value for fucoidan was valued at US$ 65.75 million and is projected to reach US$ 147.9 million by 2031, with a CAGR of 9.5 % from 2024 to 2031 [²⁶²]. This substantial growth is driven by the increasing consumer interest in natural health products, expanding applications in foods, beverages, and supplements, and promising research on fucoidan's medical benefits.

Similarly, the global laminarin market was valued at USD 2.4 million in 2023 and is projected to reach USD 4.5 million by the end of 2030, growing at a CAGR of 8.5 % [²⁶³]. This increase in demand for laminarin in the food and beverage industry is due to its health benefits and growing popularity in the pharmaceutical industry for its antioxidant, immunomodulatory, anticancer, moisturizing, and anti-aging properties.

In addition, the global alginate market size was valued at USD 849.5 million in 2023 and is projected to reach USD 1251.4 million by 2032, demonstrating a CAGR of 4.5 % from 2024 to 2032 [²⁶⁴]. This robust growth is due to alginate's increasing use as a natural stabilizer in the food and beverage industry, expanding pharmaceutical applications for drug delivery and wound healing, and advancements in biotechnology and sustainable algae cultivation.

The market for algae-based antioxidants, including phlorotannins, phenolic acids, and flavonoids, is expected to reach USD 2231.4 million by 2029, increasing from USD 1504 million in 2023 at a CAGR of 5.8 % during the period from 2023 to 2029 [²⁶⁵]. The key market growth drivers are the high antioxidant and antiviral properties of marine-derived compounds, increasing focus on natural and sustainable products, and significant regional production and consumption trends, particularly in China.

Concurrently, the market for brown algae-based pigments is also growing. In 2023, the global fucoxanthin market size was valued at USD 209.45 million, with a projected annual growth rate of 5 % from 2024 to 2030, reaching approximately USD 294.72 million [²⁶⁶]. This growth is driven by fucoxanthin's extensive use in the food, pharmaceutical, and cosmetic industries due to its health benefits, particularly in cancer treatment.

Finally, the global market for algae fats, including algae-derived lipids like omega-3 and fucosterol, was valued at USD 297.7 million in 2023. It is projected to grow at a CAGR of 5 % from 2023 to 2033, with sales expected to exceed USD 484.5 million by 2033 [²⁶⁷]. This growth is driven by the increasing demand for algae-based functional foods, dietary supplements with high omega-3 content, and interest in algal oil for biofuel production as a sustainable alternative to fossil fuels.

The market for algal bioactive compounds is expected to grow significantly, with segments like fucoidan, laminarin, alginates, and algae-based antioxidants showing strong potential. Although specific market size estimates may vary depending on the consulted source, the overall trend suggests a promising future. Notably, alginate and phenolic compounds had the highest market values in 2023, at USD 849.58 million and 1504 million, respectively (Fig. 5). These markets are projected to continue thriving, reflecting their widespread use in food, pharmaceuticals, and cosmetics. Notably, fucoidan and laminarin show the highest CAGRs at 9.5 % and 8.5 %, respectively, indicating that these compounds are in high demand. In conclusion, the global market for algae-derived bioactive compounds is set for significant growth, fueled by their wide-ranging applications and rising consumer demand for natural, sustainable products.